Sphingosine-1-phosphate (S1P) is a lysophospholipid mediator that evokes a variety of cellular responses by stimulation of five members of the endothelial cell differentiation gene (EDG) receptor family. The EDG receptors are G-protein coupled receptors (GPCRs) and on stimulation propagate second messenger signals via activation of heterotrimeric G-protein alpha (Gα) subunits and beta-gamma (Gβγ) dimers.
Sphingosine-1-phosphate (S1P) has been demonstrated to induce cellular processes, including those that result in platelet aggregation, cell proliferation, cell morphology, tumor-cell invasion, endothelial cell chemotaxis and endothelial cell in vitro angiogenesis. Therefore, S1P receptors have been targets for therapy of, for example, wound healing and tumor growth inhibition. Sphingosine-1-phosphate is believed to signal cells in part via a set of G protein-coupled receptors named S1P1, S1P2, S1P3, S1P4, and S1P5 (formerly EDG1, EDG5, EDG3, EDG6 and EDG8, respectively). These receptors share 50-55% identical amino acids and cluster with three other receptors (LPA1, LPA2, and LPA3 (formerly EDG2, EDG4 and EDG7, respectively) for the structurally related lysophosphatidic acid (LPA).
S1P receptors have been selected as drug targets because the individual receptors are both tissue and response specific. Tissue specificity of the S1P receptors is desirable because development of an agonist or antagonist selective for one receptor localizes the cellular response to tissues containing that receptor, limiting unwanted side effects. Response specificity of the S1P receptors is also of importance because it allows for the development of agonists or antagonists that can initiate or suppress certain cellular responses without affecting other responses. For example, the response specificity of the S1P receptors could allow for an S1P mimetic that initiates platelet aggregation without affecting cell morphology.
Pain can be nociceptive or neuropathic in nature. Neuropathic pain is characterized by its chronic nature, an absence of an obvious direct cause (e.g., tissue damage), hyperalgesia, or allodynia. Hyperalgesia is an exaggerated response to a painful stimulus. Allodynia is the perception of normal stimuli as painful (examples include the touch of clothing, warm or cool air, etc.). Neuropathic pain can be a sequel to nerve damage in an extremity such as an arm, or more often, a leg. Precipitating events can include trauma, e.g., motor vehicle accidents or amputations (e.g., phantom limb pain). Neuropathic pain can occur due to an adverse effect of drug therapies, e.g., vincristine or paclitaxel (Taxol™), or can occur as a component of disease pathologies, such as diabetes type 1 or type 2, shingles, HIV-1 infections, etc. Typically, neuropathic pain does not respond to opiates or non-steroidal anti-inflammatory drugs such as aspirin. Treatment of neuropathic pain is an important unmet medical need and this invention addresses that need.
There is a long felt need in the art for compounds and methods which are useful for preventing and treating pain. The present invention satisfies these needs.